NK4 exhibits two distinct
biological actions: antagonistic inhibition of
hepatocyte growth factor (HGF) through binding to the Met/
HGF receptor, and antiangiogenic action through binding to
perlecan. Here, the anti-
tumor effect of NK4 on
malignant pleural mesothelioma was investigated. Of the 7 human
malignant mesothelioma cell lines (ACC-Meso-1, ACC-Meso-4, EHMES-1, EHMES-10, H28, H2052 and JMN-1B), only EHMES-10 cells formed subcutaneous
tumors when implanted into mice. For EHMES-10 cells, HGF facilitated invasion of the cells in
collagen gel, whereas NK4 and neutralizing anti-HGF antibody suppressed the HGF-induced invasion. In addition, NK4 but not anti-HGF antibody suppressed proliferation of EHMES-10 cells in
collagen, suggesting that the suppression by NK4 was independent of the HGF-Met pathway. In the subcutaneous
tumor model, recombinant adenovirus-mediated intratumoral expression of NK4 inhibited
tumor growth, while the invasive characteristic of
tumor cells was not observed. Analysis of Met
receptor tyrosine phosphorylation, proliferation, apoptosis and blood vessels in the
tumor tissues indicated that the inhibitory effect of NK4 expression might be primarily caused by the inhibition of
tumor angiogenesis. In all the 7
mesothelioma lines, HGF stimulated Met
tyrosine phosphorylation, and this was associated with enhanced cell migration. HGF-dependent Met activation and migration were inhibited by NK4. Since
malignant pleural mesothelioma represents an aggressive
neoplasm characterized by extensive invasive growth, suppression of invasive growth has therapeutic value. Thus, the simultaneous inhibition of the HGF-Met pathway and angiogenesis by NK4 for treatment of
malignant pleural mesothelioma is significant, particularly to attenuate migration and invasive growth.